Bypass of Abasic Site–Peptide Cross-Links by Human Repair and Translesion DNA Polymerases

Yudkina, Anna V.; Barmatov, Alexander E.; Bulgakov, Nikita A.; Boldinova, Elizaveta O.; Shilkin, Evgeniy S.; Makarova, Alena V.; Zharkov, Dmitry O.

doi:10.3390/ijms241310877

Open AccessArticle

Bypass of Abasic Site–Peptide Cross-Links by Human Repair and Translesion DNA Polymerases

by

Anna V. Yudkina

^1,*,

Alexander E. Barmatov

¹,

Nikita A. Bulgakov

¹,

Elizaveta O. Boldinova

²,

Evgeniy S. Shilkin

²,

Alena V. Makarova

²

and

Dmitry O. Zharkov

^1,3,*

¹

SB RAS Institute of Chemical Biology and Fundamental Medicine, Novosibirsk 630090, Russia

²

Institute of Molecular Genetics, National Research Center “Kurchatov Institute”, Moscow 123182, Russia

³

Department of Natural Sciences, Novosibirsk State University, Novosibirsk 630090, Russia

^*

Authors to whom correspondence should be addressed.

Int. J. Mol. Sci. 2023, 24(13), 10877; https://doi.org/10.3390/ijms241310877

Submission received: 30 April 2023 / Revised: 20 June 2023 / Accepted: 27 June 2023 / Published: 29 June 2023

(This article belongs to the Collection Feature Papers in “Molecular Biology”)

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Abstract

DNA–protein cross-links remain the least-studied type of DNA damage. Recently, their repair was shown to involve proteolysis; however, the fate of the peptide remnant attached to DNA is unclear. Particularly, peptide cross-links could interfere with DNA polymerases. Apurinuic/apyrimidinic (AP) sites, abundant and spontaneously arising DNA lesions, readily form cross-links with proteins. Their degradation products (AP site–peptide cross-links, APPXLs) are non-instructive and should be even more problematic for polymerases. Here, we address the ability of human DNA polymerases involved in DNA repair and translesion synthesis (POLβ, POLλ, POLη, POLκ and PrimPOL) to carry out synthesis on templates containing AP sites cross-linked to the N-terminus of a 10-mer peptide (APPXL-I) or to an internal lysine of a 23-mer peptide (APPXL-Y). Generally, APPXLs strongly blocked processive DNA synthesis. The blocking properties of APPXL-I were comparable with those of an AP site, while APPXL-Y constituted a much stronger obstruction. POLη and POLκ demonstrated the highest bypass ability. DNA polymerases mostly used dNTP-stabilized template misalignment to incorporate nucleotides when encountering an APPXL. We conclude that APPXLs are likely highly cytotoxic and mutagenic intermediates of AP site–protein cross-link repair and must be quickly eliminated before replication.

Keywords: DNA damage; DNA repair; DNA–peptide cross-links; AP sites; DNA polymerases; translesion synthesis; DNA lesion bypass; mutagenesis

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MDPI and ACS Style

Yudkina, A.V.; Barmatov, A.E.; Bulgakov, N.A.; Boldinova, E.O.; Shilkin, E.S.; Makarova, A.V.; Zharkov, D.O. Bypass of Abasic Site–Peptide Cross-Links by Human Repair and Translesion DNA Polymerases. Int. J. Mol. Sci. 2023, 24, 10877. https://doi.org/10.3390/ijms241310877

AMA Style

Yudkina AV, Barmatov AE, Bulgakov NA, Boldinova EO, Shilkin ES, Makarova AV, Zharkov DO. Bypass of Abasic Site–Peptide Cross-Links by Human Repair and Translesion DNA Polymerases. International Journal of Molecular Sciences. 2023; 24(13):10877. https://doi.org/10.3390/ijms241310877

Chicago/Turabian Style

Yudkina, Anna V., Alexander E. Barmatov, Nikita A. Bulgakov, Elizaveta O. Boldinova, Evgeniy S. Shilkin, Alena V. Makarova, and Dmitry O. Zharkov. 2023. "Bypass of Abasic Site–Peptide Cross-Links by Human Repair and Translesion DNA Polymerases" International Journal of Molecular Sciences 24, no. 13: 10877. https://doi.org/10.3390/ijms241310877

APA Style

Yudkina, A. V., Barmatov, A. E., Bulgakov, N. A., Boldinova, E. O., Shilkin, E. S., Makarova, A. V., & Zharkov, D. O. (2023). Bypass of Abasic Site–Peptide Cross-Links by Human Repair and Translesion DNA Polymerases. International Journal of Molecular Sciences, 24(13), 10877. https://doi.org/10.3390/ijms241310877

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Bypass of Abasic Site–Peptide Cross-Links by Human Repair and Translesion DNA Polymerases

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